Intellia Therapeutics Inc (NTLA) 2022 Q4 法說會逐字稿

Good morning, and welcome to the Intellia Therapeutics Fourth Quarter and Full Year 2022 Financial Results Conference Call. My name is Drew, and I will be your conference operator today. (Operator Instructions) This conference is being recorded at the company's request and will be available on the company's website following the end of the call. (Operator Instructions)

早上好，歡迎來到 Intellia Therapeutics 第四季度和 2022 年全年財務業績電話會議。我叫德魯，今天我將擔任你們的會議接線員。 （操作員說明）本次會議是應公司要求錄製的，通話結束後將在公司網站上公佈。 （操作員說明）

I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

我現在將會議轉交給 Intellia 投資者關係和企業傳播高級副總裁 Ian Karp。請繼續。

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics fourth quarter and full year 2022 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website.

謝謝接線員，大家早上好。歡迎來到 Intellia Therapeutics 第四季度和 2022 年全年財報電話會議。今天上午早些時候，Intellia 發布了一份新聞稿，概述了公司本季度的進展以及今天電話會議的討論主題。此新聞稿可在 Intellia 網站 intelliatx.com 的投資者和媒體部分找到。該電話正在現場直播，重播將在公司網站上存檔。

At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

此時，我想花一點時間提醒聽眾，在此次電話會議期間，Intellia 管理層可能會做出某些前瞻性陳述，並要求您參考我們在 sec.gov 上提供的美國證券交易委員會文件，以討論潛在風險和不確定性.本次電話會議上提供的所有信息截至今天都是最新的，除非法律要求，否則 Intellia 不承擔更新此信息的義務。

Joining me from Intellia are Dr. John Leonard, Chief Executive Officer; Dr. David Lebwohl, Chief Medical Officer; Dr. Laura Sepp-Lorenzino, Chief Scientific Officer; and Glenn Goddard, Chief Financial Officer. John will begin with an overview of recent business highlights. David will provide an update on our clinical programs. Laura will recap the company's R&D progress across our pipeline. And Glenn will review Intellia's financial results for the fourth quarter and full year 2022. John will then offer some concluding remarks before we open up the call for Q&A.

和我一起來自 Intellia 的是首席執行官 John Leonard 博士； David Lebwohl 博士，首席醫療官； Laura Sepp-Lorenzino 博士，首席科學官；和首席財務官格倫·戈達德 (Glenn Goddard)。 John 將首先概述最近的業務亮點。大衛將提供我們臨床項目的最新信息。勞拉將回顧公司在我們管道中的研發進展。 Glenn 將審查 Intellia 第四季度和 2022 年全年的財務業績。John 將在我們開始問答之前發表一些總結性意見。

With that, I'll now turn the call over to John.

有了這個，我現在將電話轉給約翰。

Thank you, Ian, and thank you all for joining us this morning. At Intellia, we're advancing our leadership position as the industry's most innovative genome editing company with the broadest and deepest toolbox of novel editing and delivery solutions. 2022 proved to be another outstanding year for Intellia with several significant clinical milestones achieved across our pipeline. Having demonstrated human proof-of-concept for our first 2 in vivo clinical candidates, NTLA-2001 and NTLA-2002, we're now 2 for 2. Notably, we've dosed more than 50 patients with our in vivo CRISPR-based therapies in ongoing clinical studies with durability and safety data now out 2 years in the earliest patients. These accomplishments reflect steady execution against our core strategy to harness the immense power of CRISPR-based technologies both for in vivo and ex vivo applications.

謝謝你，伊恩，感謝大家今天早上加入我們。在 Intellia，我們正在提升我們作為業界最具創新性的基因組編輯公司的領導地位，擁有最廣泛和最深入的新穎編輯和交付解決方案工具箱。事實證明，2022 年對 Intellia 來說又是傑出的一年，我們的管道實現了幾個重要的臨床里程碑。在為我們的前 2 個體內臨床候選者 NTLA-2001 和 NTLA-2002 展示了人類概念驗證後，我們現在是 2 對 2。值得注意的是，我們已經對 50 多名患者進行了基於體內 CRISPR 的給藥正在進行的具有耐久性和安全性數據的臨床研究中的療法現在已經在最早的患者中使用了 2 年。這些成就反映了我們在體內和體外應用中利用基於 CRISPR 技術的巨大力量的核心戰略的穩步執行。

Building on last year's strong momentum, we have already hit the ground running this year. We're pleased to share today that we initiated the Phase II portion of the NTLA-2002 study outside of the U.S. Recently, we also submitted an IND application to the FDA to enable U.S. patient enrollment in this trial. We're highly encouraged by the rapid progress we have made in just the past few months and expect to hear back from the FDA in the coming weeks.

在去年的強勁勢頭的基礎上，我們今年已經開始運行。我們今天很高興地與大家分享，我們在美國以外啟動了 NTLA-2002 研究的 II 期部分。最近，我們還向 FDA 提交了 IND 申請，以使美國患者能夠參與該試驗。我們對過去幾個月取得的快速進展感到非常鼓舞，並希望在未來幾週內收到 FDA 的回复。

Looking ahead, for NTLA-2001, we're poised to submit an IND application for a pivotal trial for the cardiomyopathy manifestation of ATTR amyloidosis mid-year with a trial initiation anticipated by the end of the year, subject of course to regulatory feedback. Importantly, we look forward to presenting new interim clinical updates from both ongoing NTLA-2001 and NTLA-2002 first-in-human studies this year.

展望未來，對於 NTLA-2001，我們準備在年中提交一項 IND 申請，以進行一項針對 ATTR 澱粉樣變性心肌病表現的關鍵試驗，預計在今年年底開始試驗，當然要接受監管反饋。重要的是，我們期待著展示今年正在進行的 NTLA-2001 和 NTLA-2002 首次人體研究的新中期臨床更新。

Turning to our research pipeline. We are advancing new platform capabilities to the clinic. This includes our CRISPR-based in vivo targeted gene insertion technology and a first-of-its-kind allogeneic cell engineering solution designed to avoid both T cell and NK cell-mediated rejection. Additionally, we're leading the development of new gene editing and delivery modalities, which will drive further pipeline growth and allow us to reach a greater number of patients with our genetic medicines.

轉向我們的研究渠道。我們正在向診所推進新的平台功能。這包括我們基於 CRISPR 的體內靶向基因插入技術和旨在避免 T 細胞和 NK 細胞介導的排斥反應的首創同種異體細胞工程解決方案。此外，我們正在引領新的基因編輯和遞送方式的開發，這將推動管道的進一步發展，並使我們的基因藥物能夠惠及更多的患者。

With that introduction, I'll hand the call over to our Chief Medical Officer, David Lebwohl, who will review NTLA-2001 and NTLA-2002's progress in greater detail and outline updates across our clinical pipeline. David?

通過該介紹，我會將電話轉交給我們的首席醫療官 David Lebwohl，他將更詳細地審查 NTLA-2001 和 NTLA-2002 的進展，並概述我們臨床管道的更新。大衛？

Thanks, John, and welcome, everyone. I'll begin with a review of 2001, a potential single dose treatment that may halt and reverse the disease for people living with ATTR amyloidosis.

謝謝，約翰，歡迎大家。我將從 2001 年的回顧開始，這是一種潛在的單劑量治療，可以阻止和逆轉 ATTR 澱粉樣變性患者的疾病。

In November, we shared additional positive interim results from the cardiomyopathy arm of the ongoing Phase I clinical trial of 2001. These data, which were presented in a late-breaking oral presentation at the American Heart Association Scientific Sessions, demonstrated consistent greater than 90% serum TTR reduction following a single dose of 2001. The deep reductions were sustained with patient follow-up ranging from 4 to 6 months as of the data cutoff date.

11 月，我們分享了正在進行的 2001 年 I 期臨床試驗的心肌病組的額外積極中期結果。這些數據在美國心臟協會科學會議上的最新口頭報告中提出，證明一致的大於 90%單劑量 2001 後血清 TTR 降低。截至數據截止日期，患者隨訪 4 至 6 個月，深度降低持續存在。

2001 was generally well tolerated in all 12 patients. 2 of the 12 patients reported transient infusion reactions, which resolved quickly and which were the only observed treatment-related adverse events. No clinically significant laboratory abnormalities were observed at either dose level. We continue to believe these deep, durable and consistent levels of protein reduction support 2001's potential to be a best-in-class TTR-lowering agent, regardless of disease manifestation.

2001 在所有 12 名患者中普遍耐受良好。 12 名患者中有 2 名報告了短暫的輸液反應，該反應迅速消退，並且是唯一觀察到的與治療相關的不良事件。在任一劑量水平均未觀察到有臨床意義的實驗室異常。我們仍然相信，無論疾病表現如何，這些深度、持久和一致的蛋白質減少水平支持 2001 成為同類最佳 TTR 降低劑的潛力。

In the last few months, we completed the planned enrollment for the dose expansion portion of the cardiomyopathy and polyneuropathy arms. Data from these cohorts will be used to inform our dose selection decision for subsequent pivotal studies. For ATTR-CM, we plan to submit an IND application mid-year and plan to initiate a global pivotal study by year-end, subject to regulatory feedback. Additionally, we plan to present new and important interim clinical data later this year, including longer-term safety and durability data as well as emerging clinical endpoints. For hereditary ATTR amyloidosis with polyneuropathy, we are continuing to prepare for a Phase III study, including discussions with regulatory authorities, and look forward to presenting additional clinical data from the ongoing Phase I study.

在過去的幾個月裡，我們完成了心肌病和多發性神經病組劑量擴展部分的計劃招募。來自這些隊列的數據將用於為後續關鍵研究的劑量選擇決策提供信息。對於 ATTR-CM，我們計劃在年中提交 IND 申請，併計劃在年底前啟動一項全球關鍵研究，具體取決於監管機構的反饋。此外，我們計劃在今年晚些時候提供新的重要中期臨床數據，包括長期安全性和耐久性數據以及新出現的臨床終點。對於遺傳性 ATTR 澱粉樣變性伴多發性神經病，我們正在繼續準備 III 期研究，包括與監管機構的討論，並期待提供正在進行的 I 期研究的更多臨床數據。

I'll turn now to our second in vivo program, 2002, our investigational therapy for the treatment of hereditary angioedema, or HAE. We shared additional positive results from the ongoing Phase I/II clinical study at the American College of Allergy, Asthma and Immunology 2022 Annual Scientific Meeting this past November. The data presented demonstrated that a single dose of 2002 led to robust reductions in plasma kallikrein and HAE attack rates. For the 25 milligram and 75 milligram cohorts, these deep reductions in plasma kallikrein were sustained in all patients through data cutoff, which range from Week 16 to Week 32. Importantly, all patients dosed in these 2 cohorts who completed the prespecified 16-week observation period have maintained an attack-free status as of the data cutoff date.

現在我將談談我們的第二個體內計劃，2002 年，我們用於治療遺傳性血管性水腫 (HAE) 的研究性療法。我們在去年 11 月舉行的美國過敏、哮喘和免疫學學會 2022 年度科學會議上分享了正在進行的 I/II 期臨床研究的更多積極結果。所提供的數據表明，單劑量的 2002 會導致血漿激肽釋放酶和 HAE 發作率的大幅降低。對於 25 毫克和 75 毫克組群，血漿激肽釋放酶的這些深度減少在所有患者中持續到數據截止，範圍從第 16 周到第 32 週。重要的是，在這 2 個組群中完成預先指定的 16 週觀察的所有患者截至數據截止日期，期間一直保持無攻擊狀態。

Patients in the 50-milligram cohort have not yet completed the primary 16-week conservation period before the presentation cutoff date, and so we look forward to presenting attack rate data on this cohort later this year.

50 毫克隊列中的患者在報告截止日期之前尚未完成最初的 16 周保護期，因此我們期待在今年晚些時候提供該隊列的發病率數據。

At all 3 dose levels, 2002 is generally well tolerated, and the majority of adverse events were mild in severity. The most frequent adverse events were infusion-related reactions, which were mostly Grade 1 and resolved within 1 day. No dose-limiting toxicities, no serious adverse events, no adverse events of Grade 3 or higher and no clinically significant laboratory abnormalities were observed.

在所有 3 個劑量水平下，2002 總體上耐受性良好，大多數不良事件的嚴重程度較輕。最常見的不良事件是輸液相關反應，大部分為 1 級並在 1 天內解決。沒有劑量限制性毒性，沒有嚴重的不良事件，沒有 3 級或更高級別的不良事件，也沒有觀察到具有臨床意義的實驗室異常。

We believe these data speak to 2002's potential to address the significant disease burden faced by people living with HAE by permanently preventing the debilitating swelling attacks with a single dose. We look forward to presenting additional data from the Phase I portion of the study in 2023, including longer-term safety, durability and attack rate data across all 3 cohorts.

我們相信這些數據表明 2002 年有可能通過單劑量永久預防使人虛弱的腫脹發作來解決 HAE 患者所面臨的重大疾病負擔。我們期待在 2023 年展示該研究第一階段的更多數據，包括所有 3 個隊列的長期安全性、耐久性和發病率數據。

As John mentioned, it's been a very productive first 2 months of the year, especially for the 2002 program. In January, Intellia was awarded the Innovation Passport in the United Kingdom for 2002, which provides entry to U.K.'s Innovative Licensing and Access Pathway. We were pleased to receive the ILAP designation, which aims to accelerate time to market and facilitate patient access to innovative medicines.

正如 John 所提到的，今年的前兩個月非常富有成效，尤其是對於 2002 計劃而言。 1 月，Intellia 獲得了英國 2002 年的創新護照，這為進入英國的創新許可和訪問途徑提供了入口。我們很高興獲得 ILAP 稱號，該稱號旨在加快上市時間並促進患者獲得創新藥物。

Today, we announced that Intellia has initiated patient screening in the Phase II portion of the study in New Zealand. The Phase II portion, a randomized, placebo-controlled expansion study, is evaluating 2 doses; 25 milligrams and 50 milligrams. We anticipate expanding country and site participation in the coming months. To support inclusion of patients in the United States, Intellia recently submitted an IND application to the FDA, and we look forward to providing you with an update on the status of that application's review. As 2001 and 2002 continue to progress, we believe we are moving closer to setting a new standard of care for people living with these serious diseases.

今天，我們宣布 Intellia 已在新西蘭的第二階段研究中啟動患者篩查。 II 期部分是一項隨機、安慰劑對照的擴展研究，正在評估 2 個劑量； 25 毫克和 50 毫克。我們預計未來幾個月將擴大國家和站點的參與度。為了支持在美國納入患者，Intellia 最近向 FDA 提交了 IND 申請，我們期待為您提供該申請審查狀態的最新信息。隨著 2001 年和 2002 年的繼續推進，我們相信我們正在更接近於為患有這些嚴重疾病的人制定新的護理標準。

I'll now hand over the call to Laura, our CFO, who'll provide updates on our R&D efforts and platform advancements.

我現在將電話轉給我們的首席財務官勞拉，她將提供有關我們研發工作和平台進步的最新信息。

Thank you, David. We're entering the next stage of growth at Intellia as we advance new platform capabilities to the clinic, such as in vivo gene insertion, our allogeneic technology and base editing.

謝謝你，大衛。隨著我們將新的平台功能推向臨床，例如體內基因插入、我們的同種異體技術和鹼基編輯，我們正在進入 Intellia 的下一增長階段。

For targeted in vivo gene insertion, we're progressing both wholly owned and partner programs, leveraging our modular insertion platform. This includes NTLA-3001, our wholly owned candidate for the treatment of AATD-associated lung disease, for which we plan to submit an IND, or IND-equivalent application, in the second half of this year. In parallel, we're advancing IND-enabling activities for NTLA-2003, our third in vivo knockout candidate, as a treatment for the liver manifestation of AATD. In collaboration with Regeneron, we're also making important progress advancing our Factor IX insertion program for people with hemophilia B.

對於有針對性的體內基因插入，我們正在推進全資和合作夥伴計劃，利用我們的模塊化插入平台。這包括我們全資擁有的治療 AATD 相關肺病的候選藥物 NTLA-3001，我們計劃在今年下半年提交 IND 或 IND 等效申請。與此同時，我們正在推進 NTLA-2003 的 IND 支持活動，NTLA-2003 是我們的第三個體內敲除候選藥物，用於治療 AATD 的肝臟表現。通過與再生元 (Regeneron) 合作，我們還在推進針對 B 型血友病患者的因子 IX 插入計劃方面取得了重要進展。

Turning to our ex vivo pipeline. We're advancing multiple programs, ours and those shared with partners utilizing our proprietary allogeneic platform. These platform capabilities demonstrate the already broad opportunity of our robust research engine, but there is still more potential, and so we're further pushing the boundaries of what therapeutic gene editing can do.

轉向我們的離體管道。我們正在推進多個項目，包括我們的項目和與合作夥伴共享的項目，利用我們專有的同種異體平台。這些平台功能證明了我們強大的研究引擎已經擁有廣闊的機會，但還有更多的潛力，因此我們正在進一步突破治療性基因編輯可以做的事情的界限。

We have made rapid and significant headway with the development of our proprietary DNA writing technology. Since the acquisition of Rewrite Therapeutics, we have implemented and expanded the platform, leveraging Intellia's genome editing toolbox and expertise and demonstrated robust performance and versatility. We're excited by the potential of our newest platform capability, offering us the potential to target diseases beyond those currently being explored in our pipeline.

我們在專有 DNA 寫入技術的開發方面取得了快速而重大的進展。自收購 Rewrite Therapeutics 以來，我們已經實施和擴展了該平台，利用 Intellia 的基因組編輯工具箱和專業知識，並展示了強大的性能和多功能性。我們對我們最新平台功能的潛力感到興奮，它為我們提供了針對目前正在探索的疾病之外的疾病的潛力。

I'll now hand over the call to Glenn, our CFO, who will provide an overview of our fourth quarter and full year 2022 financial results.

我現在將電話轉給我們的首席財務官格倫，他將概述我們第四季度和 2022 年全年的財務業績。

Thank you, Laura. Good morning, everyone. Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform.

謝謝你，勞拉。大家，早安。 Intellia 繼續保持強大的資產負債表，使我們能夠在我們的管道和平台上執行。

Our cash, cash equivalents and marketable securities were $1.3 billion as of December 31, 2022, compared to $1.1 billion as of December 31, 2021. The increase was driven by $337.9 million from our December follow-on offering, $227.9 million of net proceeds from the company's At the Market program, and $17.2 million in proceeds from employee-based stock plans. The increase was offset in part by cash used to fund operations of approximately $372.8 million and the acquisition of Rewrite Therapeutics for $45 million.

截至 2022 年 12 月 31 日，我們的現金、現金等價物和有價證券為 13 億美元，而截至 2021 年 12 月 31 日為 11 億美元。這一增長是由於我們 12 月後續發行的 3.379 億美元、2.279 億美元的淨收益公司的 At the Market 計劃，以及 1720 萬美元的員工股票計劃收益。這一增長被用於為運營提供資金約 3.728 億美元的現金和以 4500 萬美元收購 Rewrite Therapeutics 部分抵消。

Our collaboration revenue increased by $0.7 million to $13.6 million during the fourth quarter of 2022 compared to $12.9 million during the fourth quarter of 2021.

2022 年第四季度，我們的協作收入增加了 70 萬美元，達到 1360 萬美元，而 2021 年第四季度為 1290 萬美元。

Our R&D expenses increased by $28.9 million to $100 million during the fourth quarter of 2022 compared to $71.2 million during the fourth quarter of 2021. This increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs.

我們的研發費用在 2022 年第四季度增加了 2890 萬美元，達到 1 億美元，而 2021 年第四季度為 7120 萬美元。這一增長主要是由於我們的主導項目的推進和支持這些項目的人員增長。

Our G&A expenses increased by $1.5 million to $23.6 million during the fourth quarter of 2022 compared to $22.1 million during the fourth quarter of 2021. This increase was primarily related to employee-related expenses. Finally, we expect our cash balance to fund our operating plans beyond the next 24 months.

我們的 G&A 費用在 2022 年第四季度增加了 150 萬美元，達到 2360 萬美元，而 2021 年第四季度為 2210 萬美元。這一增長主要與員工相關費用有關。最後，我們預計我們的現金餘額將為未來 24 個月以後的運營計劃提供資金。

With that, I will now turn the call back over to John for closing remarks.

有了這個，我現在將把電話轉回給約翰作結束語。

Thank you, Glenn. As you can see, we're making steady progress towards executing against our strategic priorities, which are focused on late-stage development of our CRISPR-based therapies while continuing to innovate and bring forward new platform capabilities. This year, we look forward to advancing the Phase II portion of the NTLA-2002 study and expect to add U.S. clinical sites. We're also focused on preparing for the initiation of a global pivotal trial of NTLA-2001 for patients with the cardiomyopathy manifestation of ATTR amyloidosis. For both programs, we plan to provide further updates in the coming months. As we continue to deliver on the promise of gene editing, we maintain our broader vision for Intellia by rapidly expanding the reach of our platform to accelerate the impact on patients.

謝謝你，格倫。正如您所看到的，我們在執行我們的戰略重點方面取得了穩步進展，這些重點是我們基於 CRISPR 的療法的後期開發，同時繼續創新並推出新的平台功能。今年，我們期待推進 NTLA-2002 研究的 II 期部分，並期望增加美國臨床試驗點。我們還專注於準備啟動一項針對 ATTR 澱粉樣變性心肌病表現患者的 NTLA-2001 全球關鍵試驗。對於這兩個項目，我們計劃在未來幾個月內提供進一步的更新。隨著我們繼續兌現基因編輯的承諾，我們通過迅速擴大我們平台的範圍來加速對患者的影響，從而保持我們對 Intellia 更廣闊的視野。

With that, we'd be happy to answer any questions. Operator, you may now open the call for Q&A.

有了這個，我們很樂意回答任何問題。接線員，您現在可以打開電話進行問答。

(Operator Instructions) The first question comes from Maury Raycroft with Jefferies.

（操作員說明）第一個問題來自 Jefferies 的 Maury Raycroft。

Congrats on the progress. I was going to ask about the HAE IND. Wondering if you're commenting any more on what exactly FDA requested to be in the IND and what you included in the IND for the Phase II. And do you expect a typical IND acceptance timeline for that program?

祝賀進步。我想問一下 HAE IND。想知道您是否對 FDA 要求在 IND 中包含的內容以及您在 II 期 IND 中包含的內容髮表了更多評論。您是否期望該計劃有一個典型的 IND 驗收時間表？

Maury, thanks for your question. It's pretty standard application and aligns with some of the comments we've made in prior communications of what FDA is looking for. I think where this IND may differ from other INDs is that we're pretty far along from a clinical point of view, and we were able to supply clinical information from the ongoing study done outside the United States. So we were, of course, careful to provide a very, very careful and complete update of that information. But otherwise, I would say it's pretty standard stuff.

莫里，謝謝你的問題。這是非常標準的應用程序，並且與我們在 FDA 正在尋找的內容的先前通信中所做的一些評論一致。我認為這個 IND 與其他 IND 的不同之處在於，我們從臨床角度來看還差得很遠，而且我們能夠從美國以外正在進行的研究中提供臨床信息。因此，我們當然非常謹慎地對該信息進行了非常、非常仔細和完整的更新。但除此之外，我會說這是非常標準的東西。

Okay. And maybe one follow-up. Just if you could talk a little bit more about the Phase II design and types of patients and how you can leverage the data for a potential streamlined pivotal study in HAE.

好的。也許還有一個後續行動。如果您能多談談 II 期設計和患者類型，以及如何利用這些數據在 HAE 中進行潛在的簡化關鍵研究。

So David, do you want to address that?

大衛，你想解決這個問題嗎？

Yes. So the Phase II, we've shown it publicly. It's in our slides. But basically, it's 3 arms. There'll be an arm at 25 milligrams, an arm at 50 milligrams and a placebo arm. And the size, it's 10, 10 and 5 patients. And the idea here is to select the dose for the pivotal study. We have obviously some very good information already from the Phase I, seeing really excellent results at all 3 doses. 50 and 70 looked very much the same in terms of pharmacokinetics, so we did choose the lower dose, possibly being a safer dose. And the 25-milligram dose as well was quite good, but did look a little different in terms of pharmacokinetics. So that's really the trial. It will be informing our Phase III, which we are already thinking about the design and getting ready for. It will contribute to the eventual BLA by additional information about patients. But that's the main use of the trial.

是的。所以第二階段，我們已經公開展示了它。它在我們的幻燈片中。但基本上，它是 3 個手臂。將有一個 25 毫克的手臂，一個 50 毫克的手臂和一個安慰劑手臂。大小分別為 10、10 和 5 名患者。這裡的想法是為關鍵研究選擇劑量。我們顯然已經從第一階段獲得了一些非常好的信息，在所有 3 劑中都看到了非常好的結果。 50 和 70 在藥代動力學方面看起來非常相似，所以我們確實選擇了較低的劑量，可能是更安全的劑量。 25 毫克的劑量也很好，但在藥代動力學方面看起來確實有點不同。所以這才是真正的考驗。它將通知我們的第三階段，我們已經在考慮設計並為此做好準備。它將通過有關患者的其他信息為最終的 BLA 做出貢獻。但這是試用版的主要用途。

I'll hop back in the queue.

我會跳回到隊列中。

The next question comes from Greg Harrison with Bank of America.

下一個問題來自美國銀行的格雷格哈里森。

I wanted to ask how you're thinking about the future of the curative sickle cell landscape now that some competitors have discontinued investment in the space. What do you think will be the next step beyond the CRISPR Vertex approach, and how do you win there?

我想問一下，既然一些競爭對手已經停止對該領域的投資，您如何看待鐮狀細胞治療領域的未來。您認為 CRISPR Vertex 方法之外的下一步是什麼，您如何在這方面取勝？

Yes, thanks for the question. It's an important one and one that we certainly thought about even from the early stage of the company. I think what we've seen is that sickle cell is curable. I mean, that question in our judgment has been answered, and I think that's great news for patients. The challenge for those patients, however, is the nature of that cure. The editing, I think, is in hand. It's the application of that editing that -- where we believe we can make significant progress.

是的，謝謝你的提問。這是一個重要的問題，我們甚至從公司的早期階段就開始考慮了。我認為我們所看到的是鐮狀細胞是可以治癒的。我的意思是，我們判斷中的那個問題已經得到解答，我認為這對患者來說是個好消息。然而，這些患者面臨的挑戰是治癒的性質。我認為，編輯工作已在手頭。正是這種編輯的應用——我們相信我們可以取得重大進展。

So we've been focused really since the outset as we thought about that disease, doing it in an in vivo setting where one can avoid a bone marrow transplant and the morbidity and occasional mortality that comes with that. That's a more general solution for patients. And in fact, I think it's a very, very broad-based solution even for patients outside the standard western markets where most patients with sickle cell reside. So that's where we focused our efforts. And from our perspective, based on what we've seen, that space is wide open, and we intend to get there first.

所以我們從一開始就非常關注這種疾病，在體內環境中進行，這樣可以避免骨髓移植以及隨之而來的發病率和偶發死亡率。這是對患者更通用的解決方案。事實上，我認為這是一個非常非常廣泛的解決方案，即使對於大多數鐮狀細胞患者所在的標準西方市場以外的患者也是如此。所以這就是我們集中精力的地方。從我們的角度來看，根據我們所看到的，這個空間是敞開的，我們打算首先到達那裡。

That's helpful.

這很有幫助。

The next question comes from Joon Lee with Truist Securities.

下一個問題來自 Truist Securities 的 Joon Lee。

This is [Ametia] on for Joon. So I will follow up on the previous question and asking like what is your strategy now? Is that you're following the same type of edits for sickle cell? And what would be your delivery mechanism? And I have a quick follow-up question.

這是 Joon 的 [Ametia]。因此，我將跟進上一個問題並詢問您現在的策略是什麼？您是否正在對鐮狀細胞進行相同類型的編輯？您的交付機制是什麼？我有一個快速的後續問題。

Well, thanks again. Our strategy hasn't changed for some years now. And we've always been focused on the in vivo setting. Just to be clear with respect to the Novartis news, that was an ex vivo only application and one that has been followed by them and others in the space. For us, we've always focused on the in vivo setting. From an editing point of view, we think there's any number of potential edits that can be successful. And our particular approach is not one that we've disclosed. But what I think we've learned is that the disease is curable. So it's really a matter of delivery and making sure that that's done in a way that is robust and works well for patients.

嗯，再次感謝。我們的戰略多年來一直沒有改變。我們一直專注於體內環境。關於諾華的消息，需要明確的是，那是一種僅在體外的應用，並且已經被他們和該領域的其他人跟進。對我們來說，我們一直專注於體內環境。從編輯的角度來看，我們認為有任何數量的潛在編輯都可以成功。我們的特殊方法不是我們已經披露的方法。但我認為我們已經了解到這種疾病是可以治癒的。因此，這實際上是一個交付問題，並確保以一種穩健且對患者有效的方式完成交付。

Awesome. And could you please provide some color on your in writing system? Any idea, is it similar to existing techniques out there like PASTE and PE, or is it more similar to homologous recombination? Any color in that domain would be appreciated.

驚人的。你能在你的書寫系統上提供一些顏色嗎？任何想法，它是否類似於 PASTE 和 PE 等現有技術，或者它是否更類似於同源重組？該領域中的任何顏色都將不勝感激。

Yes. We're not disclosing the specifics. We think about it in terms of capabilities, which is the resulting gene edit. In our case, we're most interested in what the resulting change in the DNA is. And the specifics of how you get there, the particular enzyme system is proprietary and one that we've worked to develop. So we're excited about our ability to introduce the intended changes and do that with great fidelity and great specificity and great activity, frankly. So as we go on and the results mirror it, we will be in a position to share more about the progress we're making. But needless to say, as Laura made clear in her remarks, we're very, very excited about where we are and where we're headed.

是的。我們沒有透露具體細節。我們從能力的角度來考慮它，這就是由此產生的基因編輯。在我們的例子中，我們最感興趣的是 DNA 的變化是什麼。以及你如何到達那裡的細節，特定的酶系統是專有的，我們一直在努力開發。因此，坦率地說，我們很高興能夠引入預期的變化，並以高保真度、高特異性和高活性來做到這一點。因此，隨著我們繼續進行並且結果反映出來，我們將能夠更多地分享我們正在取得的進展。但毋庸置疑，正如勞拉在她的發言中明確表示的那樣，我們對我們所處的位置和前進的方向感到非常非常興奮。

The next question comes from Swapnil Malekar with Piper Sandler.

下一個問題來自 Swapnil Malekar 和 Piper Sandler。

So you had previously mentioned the likelihood of having an interim readout for the pivotal trial in ATTR cardiomyopathy. So I was just wondering like how the new emerging data and the new emerging clinical endpoints that you mentioned in the press release are informing this decision of an interim analysis.

所以你之前提到過對 ATTR 心肌病的關鍵試驗進行中期讀數的可能性。所以我只是想知道你在新聞稿中提到的新出現的數據和新出現的臨床終點如何為中期分析的決定提供信息。

David, do you want to address that? Just to be clear, we're not talking about sharing interim results of a pivotal trial. Maybe, David, you could just clarify what our plans are with data disclosures for the ongoing study.

大衛，你想解決這個問題嗎？需要明確的是，我們並不是在談論分享關鍵試驗的中期結果。也許，大衛，你可以澄清我們對正在進行的研究的數據披露的計劃。

Sorry. I meant just in terms of clinical trial design, if there will be an interim analysis.

對不起。我的意思是就臨床試驗設計而言，是否會有中期分析。

Okay. Yes. So for the Phase III, as you know, we're designing that now. We're not talking about the exact details. So we have said that we think the important endpoints are cardiovascular events and mortality. And we've seen some of the other trials out there. It does have to be a large trial to study these questions. We'll have a big advantage as we start to do our trial, and that we may see early results from the other trials, which will help inform how we design this trial. But we are considering whether an interim analysis would be valuable here. Because we have the best reduction in TTR, we also expect to have the best efficacy in that trial. And because of that, the trial could be positive in interim analysis, and we're looking carefully at that possibility.

好的。是的。所以對於第三階段，正如你所知，我們現在正在設計。我們不是在談論確切的細節。所以我們說過，我們認為重要的終點是心血管事件和死亡率。我們已經看到了其他一些試驗。研究這些問題確實需要大試驗。當我們開始進行試驗時，我們將擁有很大的優勢，我們可能會看到其他試驗的早期結果，這將有助於我們設計該試驗的方式。但我們正在考慮中期分析在這裡是否有價值。因為我們在 TTR 上有最好的降低，所以我們也期望在該試驗中有最好的療效。因此，該試驗在中期分析中可能是積極的，我們正在仔細研究這種可能性。

Got it. And one follow-up I had is, so you mentioned that there have been like more than 50 patients dosed across 2 programs with some of the patients reaching 2-year mark. So I was just wondering if there were any relapses in KTR or kallikrein in any of the patients that required redosing.

知道了。我的一項後續行動是，所以你提到有超過 50 名患者在 2 個項目中接受了給藥，其中一些患者達到 2 年大關。所以我只是想知道是否有任何需要重新給藥的患者的 KTR 或激肽釋放酶復發。

Yes, I think what you've seen in all our studies is this effect seems to be permanent. We see the same reduction across time with these drugs. So based on the mechanism and based on what we're seeing clinically now, we do expect the effects to be permanent.

是的，我認為你在我們所有的研究中看到的是這種影響似乎是永久性的。我們看到這些藥物隨著時間的推移同樣減少。因此，基於該機制和我們現在在臨床上看到的情況，我們確實希望效果是永久性的。

The next question comes from Gena Wang with Barclays.

下一個問題來自巴克萊銀行的 Gena Wang。

This is Harshita on for Gena. Can you hear me okay?

這是 Gena 的 Harshita。你能聽到我說話嗎？

We can.

我們可以。

Awesome. For NTLA-2002, are you able to disclose how recently you submitted the IND? And how will you communicate to the investor community the outcome? Can we expect a press release?

驚人的。對於 NTLA-2002，您能否透露您最近提交 IND 的時間？您將如何向投資者社區傳達結果？我們可以期待新聞稿嗎？

We're not sharing when we submitted the IND. We're giving a broad update today, and so that's part of that process. But we will, of course, share the results of the FDA review when we have that information, just as we promised from the outset here. So stay tuned, and hopefully we'll have some favorable results to report.

我們在提交 IND 時沒有分享。我們今天要進行廣泛的更新，所以這是該過程的一部分。但是，我們當然會在獲得該信息後分享 FDA 審查的結果，正如我們從一開始就承諾的那樣。所以請繼續關注，希望我們能報告一些有利的結果。

Okay. Great. And I had a very quick follow-up. On 2001, in the prepared remarks, I think David mentioned to expect new emerging data on other endpoints like later in 2023. Can you elaborate what other endpoints that we can expect data on? That would be great.

好的。偉大的。我有一個非常快速的跟進。 2001 年，在準備好的發言中，我認為 David 提到期望在 2023 年晚些時候在其他端點上出現新的數據。您能否詳細說明我們可以在哪些其他端點上期望數據？那太好了。

David, what lies in store?

大衛，接下來會發生什麼？

Yes. So what we're looking at, the patients who've been longest on the trial, where we would possibly have the most information of the patients with polyneuropathy. Some things we've looked at in those patients include the NIS score, the NIS, which is slightly different from the mNIS+7, but gives similar information on the neuropathy symptoms. Another thing we're looking at is cardiac amyloid. This is present both in polyneuropathy patients and in the CM patients. So those are the type of things that we may have enough information on later this year.

是的。所以我們正在看的是，試驗時間最長的患者，我們可能會獲得多發性神經病患者的最多信息。我們在這些患者身上看到的一些東西包括 NIS 評分，NIS，它與 mNIS+7 略有不同，但提供了關於神經病變症狀的相似信息。我們正在研究的另一件事是心臟澱粉樣蛋白。這在多發性神經病患者和 CM 患者中均存在。所以這些是我們今年晚些時候可能有足夠信息的事情。

The next question comes from Terence Flynn with Morgan Stanley.

下一個問題來自摩根士丹利的特倫斯弗林。

I was just wondering, as you think broadly about the pipeline, I know you did the Rewrite Therapeutics deal. But just thinking more broadly, do you think there's a need for any additional business development? Or do you think you have all the tools you need at this point, John? And then one kind of second question, which again, not sure if it's applicable or not. But yesterday, a CRO announced some supply chain issues with non-human primates, and I was just wondering if that might impact any of your preclinical work or timelines.

我只是想知道，當你廣泛考慮管道時，我知道你做了 Rewrite Therapeutics 交易。但是從更廣泛的角度考慮，您認為是否需要任何額外的業務發展？還是您認為此時您擁有所需的所有工具，約翰？然後是第二個問題，同樣不確定它是否適用。但是昨天，一家 CRO 宣布了一些非人類靈長類動物的供應鏈問題，我只是想知道這是否會影響您的任何臨床前工作或時間表。

Yes. Thanks for the question. Yes, we read the same news and have inquired. We're not aware today that there's any impact on the work that we're doing. And we hope that that doesn't change, but that's the current situation.

是的。謝謝你的問題。是的，我們看到了同樣的新聞並進行了詢問。我們今天並不知道這對我們正在做的工作有任何影響。我們希望這不會改變，但這就是目前的情況。

With respect to BD, we think about it 2 ways, I guess. You asked about it in terms of tools. An important part of our strategy is to have a toolbox that is complete. And we think about that in terms of the capabilities, in terms of those different changes that we want to be able to introduce into DNA. We think we've got a great toolbox. We watch what's happening on the outside. We have our own scientific efforts internally and look for new capabilities that we think would augment the toolbox. At this point, we're pretty satisfied with the things that we want to do, but of course, we'll keep our eyes open.

關於 BD，我想我們有兩種方式來考慮它。你問的是工具方面的問題。我們戰略的一個重要部分是擁有一個完整的工具箱。我們從能力的角度，從我們希望能夠引入 DNA 的那些不同變化的角度來考慮這一點。我們認為我們有一個很棒的工具箱。我們觀察外面發生的事情。我們在內部有自己的科學努力，並尋找我們認為可以擴充工具箱的新功能。在這一點上，我們對我們想做的事情非常滿意，但當然，我們會保持警惕。

I think the broader approach to BD for us is just thinking about deploying that toolbox, not bringing things into it. What we're seeing is all kinds of wonderful opportunities, some of which we're advancing ourselves, some of which we're advancing with collaborators. And in the last 18 months, we've had 4 different collaborators that -- for different collaborations that we've struck to augment the work that we do in our own pipeline. So whether it's ophthalmology with sparing vision, autoimmune disease with Kyverna, our spinout with AvenCell, or work in NK cells with ONK, these are really exciting applications of the capabilities already in hand, and we expect to do more.

我認為對我們來說，更廣泛的 BD 方法只是考慮部署該工具箱，而不是將東西帶入其中。我們看到的是各種美妙的機會，其中一些是我們自己推進的，其中一些是我們與合作者一起推進的。在過去的 18 個月裡，我們有 4 位不同的合作者——他們進行了不同的合作，以加強我們在自己的管道中所做的工作。因此，無論是保留視力的眼科、Kyverna 的自身免疫性疾病、我們與 AvenCell 的分拆，還是與 ONK 在 NK 細胞中的合作，這些都是現有能力的真正令人興奮的應用，我們期待做更多。

And I think if you step back and look at our pipeline, and bear in mind the clinical rights that we have, commercial rights that we have from, each of those different collaborations, you'll see that this is, especially for a company like ours, of this size, a wonderful pipeline that's replete with opportunities. So BD, yes. Toolbox good with a lot of internal work going to make sure that it remains unsurpassed.

我認為，如果你退後一步，看看我們的管道，並記住我們擁有的臨床權利，我們從這些不同的合作中獲得的商業權利，你會發現這是，特別是對於像這樣的公司我們的，如此規模，一個充滿機會的美妙管道。所以 BD，是的。工具箱很好，有很多內部工作將確保它保持無與倫比。

The next question comes from Luca Issi with RBC.

下一個問題來自 RBC 的 Luca Issi。

Congrats on all the progress. This is Lisa on for Luca. Just one on the cardiomyopathy pivotal trial. Just wondering if we should expect 2 trials here, maybe one with the 6-minute walk test as the primary endpoint and another with cardiovascular-based outcome study. And maybe on sickle cell disease, can you expand further on why Novartis decided to discontinue the program? And if there's any clinical data available, will you be in a position to share it?

祝賀所有的進步。這是 Luca 的 Lisa。只有一項關於心肌病的關鍵試驗。只是想知道我們是否應該在這裡進行 2 項試驗，也許一項以 6 分鐘步行測試作為主要終點，另一項以心血管為基礎的結果研究。也許關於鐮狀細胞病，你能否進一步解釋為什麼諾華決定停止該項目？如果有任何可用的臨床數據，您能否分享？

Yes. I can't speak to Novartis' decision, other than they've been going through what appears to be a broad review of their pipeline and their different approaches to it. I would just remind you that for us, that has been a Novartis-only program, one that we've not directly participated in. We provided reagents to them some years ago. We've always believed that the future lies with the in vivo approaches, and that's been a focus of the work that we do. I'm sure they looked at the ex vivo space and may have had some of the same realizations that we had some years ago. So I think it's apparent where that space will ultimately go. But David, maybe you can answer the question about pivotal trials. How many do you actually want to do?

是的。我不能說諾華的決定，除了他們一直在經歷似乎是對他們的管道及其不同方法的廣泛審查。我只想提醒你，對我們來說，那是一個只有諾華公司的項目，我們沒有直接參與。幾年前我們向他們提供了試劑。我們一直相信，未來在於體內方法，這一直是我們所做工作的重點。我敢肯定他們看過離體空間，並且可能與我們幾年前有一些相同的認識。所以我認為這個空間最終將走向何方是顯而易見的。但是大衛，也許你可以回答關於關鍵試驗的問題。你真正想做多少？

Right. We're -- again, we're not telling the exact program, but we don't think that dividing those things into 2 trials is a great idea going forward. The 6-minute walk test, there's been more questions about how valuable it is to understanding how patients are doing, and you've seen that in some of the recent trials in amyloidosis. But again, we think the important endpoint's the cardiovascular events and mortality. And that's what the patients are interested in, the doctors are interested in, the payers are interested in. So it's really what we're most interested. The regulators, of course, are very interested in those factors.

正確的。我們——再一次，我們沒有告訴確切的計劃，但我們認為將這些事情分成 2 個試驗並不是一個好主意。 6 分鐘步行測試，關於它對了解患者的表現有多大價值的問題越來越多，你已經在最近的一些澱粉樣變性試驗中看到了這一點。但同樣，我們認為重要的終點是心血管事件和死亡率。這就是患者感興趣的，醫生感興趣的，付款人感興趣的。所以這真的是我們最感興趣的。當然，監管機構對這些因素非常感興趣。

The next question comes from Yanan Zhu with Wells Fargo.

下一個問題來自富國銀行的 Yanan Zhu。

On the HAE program, I was wondering what's the reason or rationale for having this placebo arm in this Phase II study? And also, in terms of the goal of the treatment for this kind of onetime treatment approach, are you -- do you think a complete cure is kind of the expected outcome for this type of approach, or there could be a different kind of outcome and still appropriate for this approach?

關於 HAE 計劃，我想知道在這項 II 期研究中使用安慰劑組的原因或原理是什麼？而且，就這種一次性治療方法的治療目標而言，您是否認為完全治愈是這種方法的預期結果，或者可能會有不同的結果並且仍然適合這種方法？

David, what role does placebo play, and what's the aspiration?

大衛，安慰劑起什麼作用，希望是什麼？

Sure. So the placebos are -- having placebo-controlled trials are the gold standard in randomized trials. Of course, you don't expect them to benefit in the placebo arm, but of course, you've also seen there can be a strong placebo effect in many trials. And that's the risk of not having that arm to -- not to compare. It's not a comparative trial. It's a Phase II. But it's a reference arm to see that what we expect is to have a very strong effect in both of the doses, 25 and 50, and to have little or no effect on the attack rate in the placebo arm. And that will help, again, inform and help us design the pivotal trial and choose the dose.

當然。所以安慰劑 - 安慰劑對照試驗是隨機試驗的黃金標準。當然，您不希望他們在安慰劑組中獲益，但當然，您也看到在許多試驗中可能存在很強的安慰劑效應。這就是沒有手臂去比較的風險。這不是比較試驗。這是第二階段。但它是一個參考組，可以看到我們期望在 25 和 50 兩種劑量中都有非常強的影響，並且對安慰劑組的攻擊率影響很小或沒有影響。這將再次幫助我們設計關鍵試驗並選擇劑量。

I should mention that the patients in placebo arm will be offered to cross over and get the active drug once their evaluation is completed. And of course, we do this because of the contribution they're making to our study and their desire to get this type of therapy as part of their potential cure going to the second part of this. This idea of a functional cure is what the idea that you could get to zero attacks in patients with this single treatment. And whether we can achieve that, it's too early to say. We're very encouraged by the early results. We are getting deeper reductions in kallikrein that's achieved with the best agents that are out there, so it is possible that this will also lead to better efficacy. And again, this aspiration to have a functional cure or to patients to have no attacks after receiving our drug.

我應該提一下，安慰劑組的患者在評估完成後將被提供交叉並獲得活性藥物。當然，我們這樣做是因為他們對我們的研究做出了貢獻，並且他們希望將這種療法作為他們潛在治愈方法的一部分進入第二部分。這種功能性治癒的想法就是您可以通過這種單一治療使患者零發作的想法。我們能否實現這一點，現在說還為時過早。我們對早期結果感到非常鼓舞。我們正在使用現有最好的藥物實現更深入的激肽釋放酶減少，因此這也可能會帶來更好的療效。再一次，這種希望在接受我們的藥物後獲得功能性治愈或患者不再發作的願望。

Great. If I could have a quick follow-up. On the cardiac amyloid, you mentioned that might be a readout for the 2001 program. Just wondering, is the expectation that the cardiac amyloid will be resolving? Or is the expectation that it is just stabilizing and no more additional amyloid addition?

偉大的。如果我可以快速跟進。關於心臟澱粉樣蛋白，您提到這可能是 2001 年計劃的讀數。只是想知道，是否期望心臟澱粉樣蛋白會消退？還是期望它只是穩定而不再添加額外的澱粉樣蛋白？

Yes. This hasn't been well established. Of course, there aren't therapies that get to the very low levels of TTR that we're able to achieve. But the idea we have, and we hear from the key investigators in this area, is that if you do get to low enough TTR levels, the rate of amyloid deposition into organs will be so reduced that the equilibrium will be the other way. In other words, the removal of amyloid from the heart is greater than the addition of amyloid due to the small amount of TTR that would be in the blood at that point. So that's what we're hoping to. The idea then is a possible reversal of the heart disease by getting rid of that amyloid, and that is our aspiration for that trial.

是的。這還沒有得到很好的證實。當然，沒有任何療法可以達到我們能夠達到的非常低的 TTR 水平。但是我們的想法，以及我們從該領域的主要研究人員那裡聽到的想法是，如果你確實達到足夠低的 TTR 水平，澱粉樣蛋白沉積到器官中的速度將會降低，以至於平衡將相反。換句話說，由於此時血液中的 TTR 量很少，從心臟中去除澱粉樣蛋白的效果大於添加澱粉樣蛋白的效果。這就是我們所希望的。那麼這個想法就是通過去除澱粉樣蛋白可能逆轉心髒病，這就是我們對該試驗的期望。

Next question comes from Salveen Richter with Goldman Sachs.

下一個問題來自高盛的 Salveen Richter。

This is [Shinatra] on for Salveen. Could you provide some color on the nature of discussions that you're having with regulators regarding the global pivotal study for NTLA-2001 in both ATTR-CM and PN? And also regarding NTLA-2002, how confident are you regarding the IND acceptance? And do you have any timelines in mind about when we'll get this information?

這是 Salveen 的 [Shinatra]。您能否就 ATTR-CM 和 PN 中與監管機構就 NTLA-2001 全球關鍵研究進行的討論的性質提供一些顏色？還有關於 NTLA-2002，您對 IND 接受有多大信心？關於我們何時獲得此信息，您是否有任何時間表？

Maybe David, you can address how we think about the pivotal and when we'll be in a position to share information. I just -- with respect to the IND, I would say it this way. We've had a variety of interactions with various regulators, including the FDA, in the runup to this. We believe that we're addressing the questions that they wanted us to address. It's not just the list of those questions, but it's the extent of the data that we've tried to provide that actually goes to making sure that we're not just checking boxes, but we're really answering questions and helping them to evaluate the product. Additionally, as I said at the outset, we've supplied clinical information, which I think is unique with respect to some of the other INDs that have played out over the last few years in the space. And we think that that's a helpful bit of information for the FDA to consider as they do their evaluation.

也許大衛，你可以談談我們如何看待關鍵以及我們何時能夠共享信息。我只是——關於 IND，我會這樣說。在此之前，我們與包括 FDA 在內的各種監管機構進行了各種互動。我們相信我們正在解決他們希望我們解決的問題。這不僅僅是這些問題的列表，而是我們試圖提供的數據范圍，這些數據實際上用於確保我們不只是勾選複選框，而是真正回答問題並幫助他們進行評估產品。此外，正如我一開始所說，我們提供了臨床信息，我認為這與過去幾年在該領域發揮作用的其他一些 IND 相比是獨一無二的。我們認為這是 FDA 在進行評估時考慮的有用信息。

So we look forward to the outcome. Obviously, it's subject to their review, but we think we've done a good job of robustly supplying information. And as we've said, with respect to timelines, when we have the information in terms of the outcome of that review, we will share it, and everybody will know at the same time. David, you just want to say a few words about how we approach the pivotal and when we'll be in a position to share that information?

所以我們期待結果。顯然，它需要接受他們的審查，但我們認為我們在穩健地提供信息方面做得很好。正如我們所說，關於時間表，當我們獲得有關審核結果的信息時，我們將分享它，每個人都會同時知道。大衛，你只想說說我們如何接近關鍵點以及我們何時能夠分享這些信息？

Yes. So just what John said about all aspects of our, say, the IND submission, another piece of that are clinical discussions that have gone on both in the pre-IND setting with regulators around the world, in Europe. And with that, we have -- we're coming forward with a trial design. We have the leading investigators in this area, supporting us in designing this trial. And the point at which we'll have an agreed trial, we'll have to do around the time of the IND. We've said that's the middle of the year for the IND for 2001 and as well in Europe with the CTA applications that go on for that Phase III as well. So that will be -- and the other thing we've said is that the trial will start by the end of the year. So that's sort of the time frames you have. As we have more details, we will share those with you.

是的。因此，約翰所說的關於我們的所有方面，比如 IND 提交，另一部分是在 IND 之前與歐洲世界各地的監管機構進行的臨床討論。有了這個，我們 - 我們提出了一個試驗設計。我們擁有該領域的領先研究人員，支持我們設計該試驗。我們將在 IND 期間進行商定的試驗。我們已經說過，對於 2001 年的 IND 以及歐洲的 CTA 申請，這是 III 期的年中。所以這將是——我們說過的另一件事是審判將在今年年底開始。這就是您擁有的時間範圍。當我們有更多詳細信息時，我們將與您分享。

I might add one important distinction for the listeners to keep in mind. With respect to 2001, which differs from the 2002 IND application, we're talking about an IND that would pursue a pivotal trial. So in some respects, it's not just an IND with all the preclinical work. It's also supplying the information that would typify an end of Phase II meeting with the FDA. So we expect the 2001 application to be a very, very substantial filing when we in fact do it, which is different from 2002, and it's certainly different from most of the other INDs in the space that have been for first-in-human applications. So as the year goes on, well, I'm sure we'll be talking more about this.

我可能會添加一個重要的區別，讓聽眾牢記在心。關於與 2002 年 IND 申請不同的 2001 年，我們談論的是將進行關鍵試驗的 IND。所以在某些方面，它不僅僅是一個包含所有臨床前工作的 IND。它還提供了代表與 FDA 的第二階段會議結束的信息。因此，我們預計 2001 年的申請在我們實際提交時會是一個非常非常重要的申請，這與 2002 年不同，而且它肯定與該領域的大多數其他 IND 不同，這些 IND 是針對首次人體申請的.所以隨著時間的推移，我相信我們會更多地討論這個問題。

The next question -- go ahead. Okay. The next question comes from Rick Bienkowski with Cantor Fitzgerald.

下一個問題——繼續。好的。下一個問題來自 Rick Bienkowski 和 Cantor Fitzgerald。

Congrats on all the progress. For the 2002 program, the worldwide Phase II trial initiation looks to be a bit staggered with sites outside the U.S. opening first while the IND application was submitted to the FDA. So my question is, if the FDA does have any feedback on either trial design or endpoints in the study after the IND review, are there any mechanisms to amend the trial protocol for sites outside the U.S. after the trial has already started?

祝賀所有的進步。對於 2002 年的項目，在向 FDA 提交 IND 申請時，全球 II 期試驗的啟動看起來有點錯開，美國以外的地點首先開放。所以我的問題是，如果 FDA 在 IND 審查後對研究中的試驗設計或終點有任何反饋，是否有任何機制可以在試驗已經開始後修改美國以外地點的試驗方案？

David, do you want to speak to that? I mean, I'd remind everybody, this is a Phase II study. It's not a pivotal trial. And so some of the details are less consequential. But David, do you want to speak to that?

大衛，你想談談嗎？我的意思是，我要提醒大家，這是一項 II 期研究。這不是關鍵試驗。所以一些細節就不那麼重要了。但是大衛，你想談談這個嗎？

Yes. I should say that when you're submitting a trial around the world, different regulators will often have different ideas about details of the trial, usually; not the big picture. So it is very possible that there can be amendments to the trial that occur related to feedback either in the U.S. or from outside the U.S. And sometimes it's very helpful. We think they're good ideas. Sometimes we just have to follow their direction for various reasons. But the -- yes, that certainly could happen, but there is a good mechanism for doing that, which is the amendment process for the trial.

是的。我應該說，當你在世界各地提交試驗時，通常不同的監管機構通常會對試驗的細節有不同的想法；不是大局。因此，很可能會根據美國境內或美國境外的反饋對試驗進行修改，有時這非常有幫助。我們認為它們是好主意。有時，出於各種原因，我們不得不聽從他們的指示。但是 - 是的，這肯定會發生，但是有一個很好的機制可以做到這一點，這就是審判的修正流程。

Great. Got it. And a quick follow-up. So there's a few novel technologies in the early pipeline now -- gene writing, base editing and proprietary LNPs. I guess it's difficult to get a sense of how far away all these technologies are from getting into the clinic or what sort of indications these technologies might be able to address. So are there any timelines for when we may get some more substantial updates for the progress of these earlier stage technologies?

偉大的。知道了。並進行快速跟進。因此，現在早期管道中有一些新技術——基因編寫、鹼基編輯和專有 LNP。我想很難了解所有這些技術距離進入臨床還有多遠，或者這些技術可能能夠解決哪些適應症。那麼，對於這些早期技術的進展，我們何時可以獲得更實質性的更新，是否有任何時間表？

We haven't guided to any particular products or pipelines. We've spoken generally in prior presentations about useful applications of base editing where we think it makes the most sense. That tends to fall primarily in the ex vivo setting where one is hoping to introduce many simultaneous knockouts, and we have very, very advanced work in that space. We've talked a little bit about our allogeneic platform that we're very, very excited about. And so I would encourage you to stay tuned with respect to future updates in that, and where base editing may fit in in that space, we'll see.

我們沒有指導任何特定的產品或管道。我們在之前的演講中一般性地談到了我們認為最有意義的鹼基編輯的有用應用。這往往主要落在離體環境中，人們希望在這種環境中同時引入許多基因敲除，而我們在該領域有非常非常先進的工作。我們已經談了一些我們非常非常興奮的同種異體平台。因此，我鼓勵您繼續關注未來的更新，以及鹼基編輯可能適合該領域的哪些領域，我們將拭目以待。

With the gene writing approach, it's earlier days, but we're making really excellent progress in terms of getting very high levels of specificity, and we're able to introduce the intended changes that we're looking to do. So as that moves along, we'll find what we think are the appropriate applications and talk more about that. But in the meanwhile, we're focused on progressing 2001 and 2002 and making sure that we continue to demonstrate that any of these technologies really matter for patients in a meaningful way. And that's where we think we are with the current progress. So more to come, and we'll share those updates as appropriate.

使用基因編寫方法，它還處於早期階段，但我們在獲得非常高水平的特異性方面取得了非常出色的進展，並且我們能夠引入我們想要做的預期變化。因此，隨著它的發展，我們將找到我們認為合適的應用程序，並就此進行更多討論。但與此同時，我們專注於 2001 年和 2002 年的進展，並確保我們繼續證明這些技術中的任何一項都以有意義的方式對患者真正重要。這就是我們認為我們目前取得的進展。接下來還有更多內容，我們將酌情分享這些更新。

Got it.

知道了。

A reminder to kindly keep yourself to one question. The next question comes from Raju Prasad with William Blair.

提醒您注意一個問題。下一個問題來自 Raju Prasad 和 William Blair。

Just kind of wondering the cadence of the IND submissions, why 2002 is going to come -- well, did come in ahead of 2001. Was it because, as you referred to earlier, the 2001 application's larger? I'm just wondering, because the durability and amount of data for the 2001 program on the clinical side is much higher.

只是有點想知道 IND 提交的節奏，為什麼 2002 年會到來——好吧，確實比 2001 年提前了。正如你之前提到的，是因為 2001 年的申請更大嗎？我只是想知道，因為 2001 年計劃在臨床方面的持久性和數據量要高得多。

It's really unrelated to what you're saying. It's -- 2002 is at the proper point to begin Phase II. 2001 will be at the point to begin Phase III work. And to have the information necessary to support that 2001 IND, which again, I liken to an end of Phase II meeting, a far more substantial filing than a typical first-in-human IND. Getting the full complement of clinical information, which is not just the acute exposure and the short-term editing results, but actually following these patients for some period of time, is an important part of that application. It's just the way the timelines work out. David, if you have anything to add to that? I mean, that's the essence of it.

真的和你說的沒關係。 2002 年是開始第二階段的適當時間。 2001 年將是開始第三階段工作的時間點。並獲得支持 2001 IND 所需的信息，我再次將其比作 II 期會議的結束，這是比典型的首次人體 IND 更重要的申請。獲得完整的臨床信息補充，這不僅僅是急性暴露和短期編輯結果，而是實際跟踪這些患者一段時間，是該應用程序的重要部分。這只是時間表的運作方式。大衛，你有什麼要補充的嗎？我的意思是，這就是它的本質。

No, those are the important features of the timing.

不，那些是時間的重要特徵。

Great. And maybe just a quick follow-up. Just wondering the rationale behind the ATM in Q4 on top of the follow-on. Just wondering why.

偉大的。也許只是快速跟進。只是想知道第 4 季度 ATM 背後的基本原理以及後續行動。只是想知道為什麼。

Glenn, do you want to speak to our fundraising?

格倫，你想談談我們的籌款活動嗎？

Sure. Yes. We thought the end of Q3 of last year and early Q4 was an opportune time to use the program, just based on how the stock was trading and volume. And then an opportunity opened up in late November/December to do the follow-on, we took advantage of that. So, wasn't preplanned to do it that way. It's just how things worked out.

當然。是的。我們認為去年第三季度末和第四季度初是使用該程序的合適時機，只是基於股票的交易情況和交易量。然後在 11 月下旬/12 月出現了進行後續行動的機會，我們利用了這一點。所以，沒有預先計劃那樣做。事情就是這樣發生的。

The next question comes from Dae Gon Ha with Stifel.

下一個問題來自 Stifel 的 Dae Gon Ha。

Congrats on all the progress. I'll just stick with the IND question again. So with regards to the 2002, I guess, to what extent do you think you fully address some of the FDA concerns? And we're obviously very limited to what's publicly disclosed from one of your competitor programs or peer companies. And to what extent is the depth and the extensive nature of your submission, so in the case of how many pages you submit, will that be a limitation factor as it pertains to the review within that 30-day period?

祝賀所有的進步。我將再次堅持 IND 問題。那麼關於 2002，我想，您認為您在多大程度上完全解決了 FDA 的一些擔憂？而且我們顯然非常限於從您的競爭對手計劃或同行公司之一公開披露的內容。您提交的內容的深度和廣泛性在多大程度上，那麼在您提交多少頁的情況下，這是否會成為與 30 天期限內的審核相關的限制因素？

I can't speak to the number of pages and how fast the various reviewers at the FDA read them. But -- and that's not the metric that we use. Although these applications tend to be very, very large, as you know, because there's a lot of information shared. But we try to address the questions as posed by the regulators. And I think an important thing to emphasize is it's not just data, but it's really testing the robustness of the system. And these are principles that apply not just to our space, but to drug development in general, whether you're doing small molecules, antibodies, whatever. We've tried to apply that kind of thinking, knowing from prior experience how the FDA thinks about this stuff.

我無法說出頁數以及 FDA 的各種審閱者閱讀它們的速度。但是——這不是我們使用的指標。儘管這些應用程序往往非常非常大，正如您所知，因為共享了很多信息。但我們試圖解決監管機構提出的問題。我認為需要強調的重要一點是，它不僅僅是數據，而是真正在測試系統的穩健性。這些原則不僅適用於我們的領域，而且適用於一般的藥物開發，無論你是在做小分子、抗體還是其他什麼。我們已經嘗試應用這種想法，從以前的經驗中了解 FDA 如何看待這件事。

With respect to other people, I can't address that. I don't know the work, the nature of it, et cetera. We'll see. The FDA, as they review it, I'm sure will pose questions to us. We'll do our best to answer them. But we don't expect to have major deficiencies in the IND. If there's smaller questions that they want clarification on, we will answer them as quickly and as robustly as we possibly can, but we think we have the full complement of information available.

關於其他人，我無法解決這個問題。我不知道這項工作，它的性質，等等。我們拭目以待。 FDA 在審查時肯定會向我們提出問題。我們會盡力回答他們。但我們預計 IND 不會有重大缺陷。如果他們需要澄清更小的問題，我們將盡可能快速、有力地回答他們，但我們認為我們擁有完整的可用信息。

John, just a naive question. With regards to the IND review, is there something analogous to a PDUFA extension where they just need more time to review? Or does it have to be a binary yes or clinical hold?

約翰，只是一個天真的問題。關於 IND 審查，是否有類似於 PDUFA 延期的東西，他們只需要更多時間來審查？或者它是否必須是二元的是或臨床持有？

My understanding is that it's 30 days, and you get a clearance or a hold. And then if there is a hold, there's additional information provided by the FDA in terms of what they're looking for in a very formal way. And then that's when you're in a position to best answer their follow-up. If it takes a little longer for them to go through this stuff, we'll see. But again, we believe that the full complement of information has been provided to them.

我的理解是，它是 30 天，你會得到批准或保留。然後，如果有擱置，FDA 會以非常正式的方式提供額外的信息，說明他們正在尋找什麼。然後就是您能夠最好地回答他們的後續行動的時候。如果他們需要更長的時間來完成這些事情，我們拭目以待。但同樣，我們相信已經向他們提供了完整的信息補充。

The next question comes from Debjit Chattopadhyay with Guggenheim.

下一個問題來自古根海姆的 Debjit Chattopadhyay。

Can you provide an update of how many patients have been treated across each clinical stage program, including the dose expansion cohorts?

您能否提供每個臨床階段計劃（包括劑量擴展隊列）中有多少患者接受治療的最新信息？

I think we'll keep it at the high level. Collectively, over 50 patients have been treated. A lot of the information is already out there in terms of different groups and different studies, et cetera. So most of that information is fairly current. Obviously, we continue to dose patients in the second phase of the study. And later on this year, we'll give you the full complement of that information.

我認為我們會保持高水平。共有 50 多名患者接受了治療。根據不同的群體和不同的研究等，已經有很多信息了。所以大部分信息都是最新的。顯然，我們在研究的第二階段繼續對患者進行給藥。今年晚些時候，我們將為您提供該信息的完整補充。

Next question comes from David Lebowitz with Citi.

下一個問題來自花旗銀行的 David Lebowitz。

This is [Debanjana] on for David. So we wanted to ask if you can provide us any further color with respect to the timing of data in 2023? And also, are you collecting kallikrein activity data in addition to the reduction in protein levels?

這是大衛的 [Debanjana]。所以我們想問一下，您是否可以就 2023 年的數據時間向我們提供更多顏色？而且，除了蛋白質水平的降低之外，您是否還收集激肽釋放酶活性數據？

David, do you want to speak to what we're actually collecting with 2002 with respect to kallikrein, and what is the anticipated flow of clinical data across the programs this year?

戴維，你想談談我們在 2002 年實際收集的關於激肽釋放酶的內容，以及今年跨項目的預期臨床數據流是什麼嗎？

Yes. So we are collecting both kallikrein protein and activity. We said we'll be presenting more data towards the end of the year. The important piece of that data is a dose that we haven't reported on in terms of attacks, and that's the 50 milligram dose. So recall, we went 25 to 75 and then stepped back to 50 to sort of fill in our dose response. We found 50, as I said, is good as 70. And we expect, of course, to get a similar activity to 25 and 70 because they both were able to reduce attacks to zero. But we will be reporting that later this year.

是的。所以我們正在收集激肽釋放酶蛋白和活性。我們說過我們將在年底前提供更多數據。該數據的重要部分是我們尚未報告的攻擊劑量，即 50 毫克劑量。所以回想一下，我們從 25 到 75，然後退回到 50 來填充我們的劑量反應。正如我所說，我們發現 50 和 70 一樣好。當然，我們希望獲得與 25 和 70 類似的活動，因為它們都能夠將攻擊減少到零。但我們將在今年晚些時候進行報告。

The next question comes Rich Law with Credit Suisse.

下一個問題來自瑞士信貸的 Rich Law。

HAE's Phase II studies such that the timeline is not dependent on U.S. sites? For example, if you receive a clinical hold on the IND, you can run the trial to completion in the ex-U.S.?

HAE 的 II 期研究使得時間表不依賴於美國網站？例如，如果您收到 IND 的臨床暫停，您可以在美國以外的地方進行試驗直至完成？

We can.

我們可以。

Mr. Law, can you please repeat your question?

羅先生，可否請您重複您的問題？

Yes, sorry. So the question is that you designed HAE Phase II study such that the timeline is not dependent on the U.S. sites. So if you get a clinical hold from for the IND, you can run the entire Phase II study outside the U.S., and it wouldn't affect the overall development trial completion.

是的，對不起。所以問題是你設計的 HAE II 期研究使得時間表不依賴於美國網站。因此，如果您獲得 IND 的臨床許可，您可以在美國境外進行整個 II 期研究，並且不會影響整個開發試驗的完成。

Yes. I mean the simplest answer to that question is, yes, we can. Of course, the priority is to have U.S. sites participating, and that's the expectation. And that's something we're going to work very, very hard to do.

是的。我的意思是對這個問題最簡單的回答是，是的，我們可以。當然，優先考慮的是讓美國站點參與，這是我們的期望。這是我們將要非常、非常努力地去做的事情。

And also, have you thought about what's the -- for ATTR-PN, will you use an external control group or an active control group for the pivotal?

而且，你有沒有想過 - 對於 ATTR-PN，你會使用外部控制組還是主動控制組作為關鍵？

David, are you in a position to talk about your polyneuropathy study designs?

大衛，你能談談你的多發性神經病研究設計嗎？

Yes. Again, we're not giving the exact designs. We have been very interested in all the submissions -- or all the pivotal trials so far have not used an active comparative arm. And that has to do with the rarity of this disease and the reliability of some of the historical data about what's happening in these patients. And that's been used, as you've seen in, for example, the vutrisiran submission. So we're looking at all that, and we'll be coming forward with the design that we'll talk about when we have the details.

是的。同樣，我們沒有給出確切的設計。我們對所有提交的材料都非常感興趣——或者說到目前為止所有關鍵試驗都沒有使用主動比較臂。這與這種疾病的罕見性以及有關這些患者所發生情況的一些歷史數據的可靠性有關。正如您在 vutrisiran 提交中看到的那樣，它已被使用。所以我們正在研究所有這些，我們將提出我們將在獲得細節時討論的設計。

The next question comes from Jay Olson with Oppenheimer.

下一個問題來自 Jay Olson 和 Oppenheimer。

Congrats on the progress. For 2002, can you talk about the rationale for using the 25 and 50 milligram doses in the Phase II study and any particular reason not to pursue the highest 75 milligram dose? And then are there any lessons learned or read-across from the 2002 IND that you plan to apply to the 2001 IND?

祝賀進步。對於 2002 年，您能否談談在 II 期研究中使用 25 和 50 毫克劑量的基本原理，以及不追求最高 75 毫克劑量的任何特殊原因？那麼，您是否計劃將 2002 IND 中的任何經驗教訓應用於 2001 IND？

David will speak to the doses and how we think about that. I think with respect to the read-through, we'll see. Obviously, 2002 is going in before 2001. And if there is information or feedback that we can apply, we would certainly do that. But the same basic philosophy has been applied to both of those programs with respect to prior engagement with regulatory agencies, the sorts of things that they're looking for which doesn't differ across the programs.

大衛將談到劑量以及我們對此的看法。我認為關於通讀，我們拭目以待。顯然，2002 年會早於 2001 年。如果有我們可以應用的信息或反饋，我們肯定會這樣做。但是，在與監管機構的事先接觸方面，同樣的基本理念已經應用於這兩個項目，他們正在尋找的東西在不同項目中並沒有什麼不同。

Just again, to draw the distinction, 2001 is a far more advanced clinical program. And the nature of -- the progression of the program in that IND would be moving to pivotal programs where a dose, dose selection, CMC material, a pivotal trial, et cetera, will all be part of that review, which we think will be more substantial in nature. But in terms of the basic preclinical information, we expect them to be quite similar. David, do you want to speak to the dose selection in the 2002 Phase II?

再次強調一下，2001 年是一個更先進的臨床項目。以及該 IND 計劃的性質將轉向關鍵計劃，其中劑量、劑量選擇、CMC 材料、關鍵試驗等都將成為該審查的一部分，我們認為這將是本質上更加充實。但就基本的臨床前信息而言，我們預計它們會非常相似。大衛，你想談談 2002 年 II 期的劑量選擇嗎？

Yes. So the Phase II has always planned to study 2 doses in addition to the placebo. This is the preferred method from regulatory agencies to really understand the best dose rather than picking it coming right out of Phase 1. And in this case, the 3 dose levels were all safe. They all led to zero attacks, so it made it a little more challenging. But what we did see is that the pharmacokinetics was very similar. We think we're saturating by the time we reach about 50 milligrams. So 75 milligrams looked very similar in terms of pharmacodynamics, the reduction in kallikrein reduction. And based on that, we chose the 2 -- 50 as one of the doses. This is sort of, we think, as high as you need to go to get optimal activity. We chose the 25 as a second dose. A little bit less in terms of pharmacodynamics, as you saw. Instead of reaching towards 90%, it was more like a 50% reduction in kallikrein. But we thought, again, for regulatory agencies to demonstrate that the higher dose might be better than the lower dose is important because you are going to a higher dose for the potential additional risk of going to a higher dose. All in all, the safety is so good, we're not really too concerned about that aspect of it, but that's why you do those things.

是的。所以二期一直計劃在安慰劑之外研究2個劑量。這是監管機構的首選方法，可以真正了解最佳劑量，而不是直接從第 1 階段中挑選出來。在這種情況下，3 個劑量水平都是安全的。它們都導致了零攻擊，因此它變得更具挑戰性。但我們確實看到的是藥代動力學非常相似。當我們達到大約 50 毫克時，我們認為我們已經飽和了。所以 75 毫克在藥效學方面看起來非常相似，減少了激肽釋放酶的減少。基於此，我們選擇了 2-50 作為劑量之一。我們認為，這有點像您獲得最佳活動所需的高度。我們選擇了 25 作為第二劑。如您所見，在藥效學方面要少一些。它沒有達到 90%，更像是激肽釋放酶減少了 50%。但我們再次認為，對於監管機構來說，證明高劑量可能比低劑量更好很重要，因為你要服用更高的劑量，因為服用更高劑量的潛在額外風險。總而言之，安全性非常好，我們並不太擔心這方面的問題，但這就是你做那些事情的原因。

The next question comes from Brian Cheng with J.P. Morgan.

下一個問題來自摩根大通的 Brian Cheng。

We're curious if you have any thoughts around the regulatory bar for IND clearance specifically in the U.S. for in vivo gene thing for some of the non-orphan larger disease indications compared to smaller orphan markets. Any feedback that you can provide on how the regulators are handling the risk/benefit, especially in the indications with larger TAM?

我們很好奇您是否對 IND 許可的監管欄有任何想法，特別是在美國，與較小的孤兒市場相比，一些非孤兒較大疾病適應症的體內基因事物。您可以就監管機構如何處理風險/收益提供任何反饋，尤其是在具有較大 TAM 的適應症方面？

I can't speak to how the FDA is assessing benefit/risk in terms of the actual application of an editing approach. We've tried to be very, very careful about choosing disease states in which it's pretty clear that an editing approach should benefit every single patient that is exposed to the agent. Treating risk factors, for example, has its own challenges. I think a good case can be made to do that. But when we think about at this point in the evolution of these therapies, a benefit/risk backdrop where you're dealing with mortal illnesses, or illnesses that pose great risk to patients, is the right setting to apply the particular modalities. And the FDA has shared some sense of that, I think, in guidances that they've released.

我無法說明 FDA 如何根據編輯方法的實際應用來評估收益/風險。我們在選擇疾病狀態時非常非常小心，在這種狀態下，很明顯編輯方法應該使接觸該藥物的每一位患者受益。例如，處理風險因素有其自身的挑戰。我認為這樣做是有充分理由的。但是，當我們考慮這些療法發展的這一點時，您正在處理致命疾病或對患者構成巨大風險的疾病的利益/風險背景是應用特定模式的正確設置。我認為 FDA 在他們發布的指南中分享了一些這方面的意義。

But I think the regulators, in my experience, try to take a considered view of what one can do for patients with different approaches. And so as they assess some of these other indications, those are conversations that I'm sure will play out as they're brought up one by one by the various sponsors who do that. So that would be our experience thus far.

但我認為，根據我的經驗，監管機構會嘗試考慮採用不同方法可以為患者做些什麼。因此，當他們評估其中一些其他跡象時，我相信這些對話會在不同贊助商逐一提出時展開。這就是我們迄今為止的經驗。

That's helpful.

這很有幫助。

The last question today will come from Joseph Thome with Cowen and Company.

今天的最後一個問題將來自 Joseph Thome 和 Cowen and Company。

Maybe just a first housekeeping one. Did you have a pre-IND meeting formally before the HAE INDUSTRY, or maybe why wasn't one appropriate at this time? And then just a follow-up on the CM trial. In terms of timing of that initiation, is the main gating factor just clearance of the U.S. IND? Or is there a certain amount of follow-up that you want to see from those expansion cohorts?

也許只是第一個家政服務。您是否在 HAE INDUSTRY 之前正式召開過 IND 前會議，或者為什麼此時不合適？然後只是對 CM 試驗的跟進。就啟動時間而言，主要的門控因素是否只是美國 IND 的批准？或者您是否希望從這些擴展隊列中看到一定數量的後續行動？

Maybe David can speak to the nature of our conversations with FDA in 2002. Just with respect to 2001 pivotal trial, we intend for it to be a global program, which means U.S. sites. We wouldn't begin a pivotal trial, at least the way we think about it now, without those U.S. sites. As we've said previously, what we're looking for is a very robust filing that includes extensive clinical information, tantamount to an end of Phase II filing, and that work is underway. That data collection will certainly be a part of what the application is. When you do a pivotal program, you want to have your final commercial material available to be used in that clinical trial. That's certainly part of this as well. So the program is quite advanced and moving as we had hoped. So I would stay tuned. As we have more information, we'll share it. David, do you want to say anything about 2002?

也許 David 可以談談我們在 2002 年與 FDA 的對話的性質。就 2001 年的關鍵試驗而言，我們打算將其作為一個全球計劃，這意味著美國網站。如果沒有這些美國網站，我們不會開始一項關鍵試驗，至少我們現在是這樣認為的。正如我們之前所說，我們正在尋找一個非常強大的文件，其中包括廣泛的臨床信息，相當於 II 期文件的結束，並且這項工作正在進行中。數據收集肯定是應用程序的一部分。當您執行關鍵程序時，您希望最終商業材料可用於該臨床試驗。這當然也是其中的一部分。因此，該計劃正如我們所希望的那樣非常先進和感人。所以我會繼續關注。當我們有更多信息時，我們將分享它。大衛，你想對 2002 年說點什麼嗎？

Yes. So we did have a formal pre-IND meeting for this. And we, I think as we've said before, we have -- feel we've addressed the questions that they have raised in that process.

是的。所以我們確實為此召開了一次正式的 IND 前會議。我想，正如我們之前所說的那樣，我們覺得我們已經解決了他們在該流程中提出的問題。

This concludes our question-and-answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.

我們的問答環節到此結束。我想將會議轉回 Ian Karp 的閉幕詞。

Great. And thanks so much, everyone, for joining us today and for your continued interest. And we certainly look forward to providing additional updates as we progress throughout the year. So thanks and have a great day.

偉大的。非常感謝大家今天加入我們以及您一直以來的興趣。隨著我們全年的進展，我們當然期待提供更多更新。所以謝謝，祝你有美好的一天。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連接。